Download The 2 alleles on chromosome 13q14 must be inactivated

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Self sufficiency in growth factors
Insensitivity to growth-inhibitory
signals
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize
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A class of genes that normally suppress cell
proliferation. Examples are p53 and Rb.
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Antigrowth signals can prevent cell
proliferation by 2 mechanism:
1-Cause the dividing cell go to Go phase
2-The cell enter post-mitotic
differentiated pool & lose replicative
potential
The molecular level of antigrowth signals
exert their effects on G1-S checkpoint of
the cell cycle, controlled by Rb gene
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Mutations that inactivate the tumor suppressor
gene products can release cells from growth
suppression and lead to hyper proliferation.
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In 1974 Knudson proposed
tow- hits hypothesis
Both alleles of the tumor suppressor gene
must be inactivated by mutation for
hyperproliferation to occur.
Cell become malignant if it homozygous for
the mutant gene
Recessive cancer gene
TUMOR SUPPRESSOR GENES
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RB gene13q14--- 1st TSG discovered
Present in every somatic cell in
active(hypoph.) & inactive
(hyperphosphorelated )form
Act as a brake prevent cell from moving
from G1S
When GF stimulate cell, The cyclin D,E
&CDK-phosphorelation of
RBinactivation-release the brake.
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60% of retinoblastoma (Rb) are sporadic
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40% are familial, an autosomal dominant
trait
The 2 alleles on chromosome 13q14 must be
inactivated
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Heterozygous-----one Rb gene is not
mutant no cancer)
Homozygous------two Rb genes are
mutant =cancer
Loss of hrterozygosity of normal Rb
gene
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Seen in > 70 % of human cancers
 Both alleles has to be mutated
 Usually mutation is aquired/ Viruses as
HepB,EBV,HPV
 Can be inherited (one allel is mutated)
as Li Fraumeni syndrome (25 fold increase
risk of ca by age 50)
Ataxia telangiectasia-> can not repair x-ray
caused DNA damage, ATM protein (damage
sensor) is mutated so inactivate TP53 (
TP53 is normal)
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APC gene loss lead to tumor
development, both copies must be lost.
Seen in70-80% of sporadic colon ca
APC may be normal but B catenin mutated
Inherited mutation of one allele will
develop 100-1000 of adenomatous
polyps in the colon by the age of 10 or
20ys. One or more polyps will develop
colon ca by the age of 40ys (Familial
Polyposis coli)
APC mutation lead to adenoma and more
mutation are needed for ca to develop